Daptomycin Pharmacokinetics in Blood and Wound Fluid in Critical Ill Patients with Left Ventricle Assist Devices.

Daptomycin is a cyclic lipopeptide antibiotic with bactericidal effects against multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). For critically ill patients, especially in the presence of implants, daptomycin is an important therapeutic option. Left ventricle assist devices (LVADs) can be utilized for intensive care patients with end-stage heart failure as a bridge to transplant. We conducted a single-center prospective trial with critically ill adults with LVAD who received prophylactic anti-infective therapy with daptomycin. Our study aimed to evaluate the pharmacokinetics of daptomycin in the blood serum and wound fluids after LVAD implantation. Daptomycin concentration were assessed over three days using high-performance liquid chromatography (HPLC). We detected a high correlation between blood serum and wound fluid daptomycin concentration at 12 h (IC95%: 0.64 to 0.95; r = 0.86; p < 0.001) and 24 h (IC95%: -0.38 to 0.92; r = 0.76; p < 0.001) after antibiotic administration. Our pilot clinical study provides new insights into the pharmacokinetics of daptomycin from the blood into wound fluids of critically ill patients with LVADs.

Liver function, quantified by the LiMAx test, as a predictor for the clinical outcome of critically ill patients treated with linezolid.

BACKGROUND: Critically ill patients commonly suffer from infections that require antimicrobial therapy. In previous studies, liver dysfunction was shown to have an essential impact on the dose selection in these patients. This pilot study aims to assess the influence of liver dysfunction, measured by the novel LiMAx test, on clinical outcomes in critically ill patients treated with linezolid. METHODS: Twenty-nine critically ill patients were included and treated with linezolid. Indications for linezolid therapy were secondary or tertiary peritonitis (46.7%), bloodstream infection (6.7%) and 46.7% were other infections with gram-positive bacteria. Linezolid Cmin, maximal liver function capacity (LiMAx test) and plasma samples were collected while linezolid therapy was in a steady-state condition. Furthermore, potential factors for the clinical outcome were investigated using logistic regression analysis. Clinical cure was defined as the resolution or significant improvement of clinical symptoms without using additional antibiotic therapy or intervention. RESULTS: Cured patients presented lower median linezolid Cmin yet a significantly higher mean LiMAx-value compared to the clinical failure group (1.9 mg/L vs. 5.1 mg/L) (349 µg/kg/h vs. 131 µg/kg/h). In the logistic regression model, LiMAx < 178 µg/kg/h was the only independent predictor of clinical failure with a sensitivity of 77% and specificity of 93%. CONCLUSIONS: The LiMAx test predicts clinical failure more precisely than linezolid trough levels in critically ill surgical patients. Therefore liver failure may have a stronger impact on the outcome of critically ill surgical patients than low linezolid Cmin. While linezolid Cmin failed to predict patient's outcome, LiMAx results were the only independent predictor of clinical failure.

Personalized ß-lactam dosing in patients with coronavirus disease 2019 (COVID-19) and pneumonia: A retrospective analysis on pharmacokinetics and pharmacokinetic target attainment.

ABSTRACT: Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.

The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Pharmacokinetics of tigecycline in critically ill patients with liver failure defined by maximal liver function capacity test (LiMAx).

BACKGROUND: In critically ill patients, tigecycline (TGC) remains an important therapeutic option due to its efficacy against multiresistant Gram-positive and Gram-negative bacteria. TGC is metabolized and eliminated predominantly by the liver. Critical illness-induced liver failure may have a profound impact on the pharmacokinetic of TGC. In the present study, we aimed to establish a link between the degree of liver dysfunction and TGC plasma concentration using the novel maximum liver function capacity (LiMAx) test, as a dynamic liver function test. MATERIALS/METHODS: The prospective study included 33 patients from a surgical ICU with the clinical indication for antibiotic therapy with TGC. The patients received 100 mg loading dose of TGC followed by intermittent standard doses of 50 mg q12. Blood samples for TGC plasma concentration were collected at 0.3, 2, 5, 8 and 11.5 h in a steady-state condition after at least 36 h post-standard dosage. The results were analyzed by means of a high-performance liquid chromatography (HPLC) method. Within the same day, the LiMAx test was carried out and routine blood parameters were measured. RESULTS: Peak plasma concentrations of TGC were significantly higher in patients with severe liver failure (LiMAx < 100 µg/kg/h) when compared to patients with normal liver function (LiMAx > 300 µg/kg/h). The pharmacokinetic curves revealed higher values in severe liver failure at any measured point. Moreover, LiMAx and total bilirubin were the only liver-related parameters that correlated with TGC Cmax. CONCLUSIONS: The present study demonstrates a high variability of TGC plasma concentrations in critically ill patients. The results show a significant correlation between the degree of liver dysfunction, measured by the LiMAx test, and TGC Cmax. LiMAx test may be a helpful tool beyond others for adjusting the required dosage of hepatic metabolized antibiotics in critically ill patients. Trial registry DRKS-German clinical trials register; Trial registration number: DRKS00008888; Date of registration: 07-17-2015; Date of enrolment of the first participant to the trial: 12-10-2015.

What Are the Predictors for Achieving Therapeutic Levetiracetam Serum Concentrations in Adult Neurological Patients?

BACKGROUND: Emerging studies suggest that levetiracetam pharmacokinetics can be difficult to predict in certain special patient populations, including the elderly, critically ill patients, and pregnant women. OBJECTIVE: To determine clinical characteristics that predict the attainment of target serum concentrations in a heterogeneous group of patients prescribed levetiracetam. METHODS: A retrospective observational study was conducted in adult neurological patients prescribed levetiracetam for the treatment or prophylaxis of seizures. Serum samples were collected after steady-state was reached, with a trough/steady-state serum concentration between 6 and 20 mg/L considered therapeutic. Logistic regression was used to identify significant predictors associated with the attainment of therapeutic concentrations. RESULTS: One-hundred thirty patients (63 male) were included. The median (interquartile ranges) serum trough/steady-state concentration (Cmin/ss) was 16.2 (9.8-26.1) mg/L. The dose-normalized median (interquartile range) Cmin/ss was 11.5 (7.0-16.5) mg/L. The coefficient of variation of Cmin/ss and dose-normalized Cmin/ss were 69.4% and 64.2%, respectively. A weak correlation was observed between levetiracetam Cmin/ss and patient age (r = 0.21; P = 0.020), creatinine clearance (r = -0.26; P = 0.004), and daily dose (r = 0.42; P < 0.001). Logistic regression analysis identified age and daily levetiracetam dose as significant factors predicting target Cmin/ss attainment. The influence of concomitant antiepileptic therapy was not determined. CONCLUSIONS: Age and daily dose were the most significant predictors of levetiracetam target-concentration attainment and should be considered in further investigations to develop a dosing algorithm for optimal levetiracetam therapy.

CSF penetration of vancomycin in critical care patients with proven or suspected ventriculitis: a prospective observational study.

BACKGROUND: Vancomycin is recommended for ventriculitis. However, penetration into the CNS is relatively poor. OBJECTIVES: To investigate the population pharmacokinetics of vancomycin in serum and CSF in critical care patients with proven or suspected CNS infections from neurosurgical procedures. PATIENTS AND METHODS: This was an observational pharmacokinetic study in critical care patients with proven or suspected CNS infections receiving intravenous vancomycin. Multiple blood and intraventricular CSF samples were collected. Population pharmacokinetic analysis and simulation were undertaken with ADAPT5 and Pmetrics. RESULTS: A total of 187 blood and CSF samples were collected from 21 patients. The median (range) Cmax and Cmin concentrations in serum were 25.67 (10.60-50.78) and 9.60 (4.46-23.56) mg/L, respectively, with a median daily dose of 2500 (500-4000) mg. The corresponding median concentrations in CSF were 0.65 (<0.24-3.83) mg/L and 0.58 (<0.24-3.95) mg/L, respectively. The median AUC0-24 in serum and CSF was 455.09 and 14.10 mg·h/L, respectively. A three-compartment linear population pharmacokinetic model best fitted the observed data. Vancomycin demonstrated poor penetration into CSF, with a median CSF/serum ratio of 3% and high intersubject pharmacokinetic variability of its penetration. CONCLUSIONS: Therapeutic drug monitoring in both serum and CSF and higher daily doses may be an option to ensure adequate trough levels and to optimize patient therapy. Novel dosing strategies designed to reduce renal toxicity, such as administration by continuous infusion, should be investigated in further clinical studies to avoid antibiotic underexposure in CSF.

Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model.

Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.

Linezolid in liver failure: exploring the value of the maximal liver function capacity (LiMAx) test in a pharmacokinetic pilot study.

Patients in the intensive care unit frequently require antibiotic treatment. Liver impairment poses substantial challenges for dose selection in these patients. The aim of the present pilot study was to assess the novel maximal liver function capacity (LiMAx test) in comparison with conventional liver function markers as covariates of drug clearance in liver failure using linezolid as a model drug. A total of 28 patients with different degrees of liver failure were recruited. LiMAx test as well as plasma, dialysate and urine sampling were performed under linezolid steady-state therapy (600 mg twice daily). NONMEM® was used for a pharmacometric analysis in which the different clearance routes of linezolid were elucidated. Linezolid pharmacokinetics was highly variable in patients with liver failure. The LiMAx score displayed the strongest association with non-renal clearance (CLnon-renal) [ = 4.46∙(body weight/57.9) 0.75∙(LiMAx/221.5)0.388 L/h], which reduced interindividual variability in CLnon-renal from 46.6% to 33.6%, thereby being superior to other common markers of liver function (international normalised ratio, gamma-glutaryl transferase, bilirubin, thrombocytes, alanine aminotransferase, aspartate aminotransferase). For LiMAx < 100 µg/kg/h, 64% of linezolid trough concentrations were above the recommended trough concentration of 8 mg/L, indicating the necessity of therapeutic drug monitoring in these patients. This is the first pilot application of the LiMAx test in a pharmacokinetic (PK) study demonstrating its potential to explain PK variability in linezolid clearance. Further studies with a larger patient collective and further drugs are highly warranted to guide dosing in patients with severe liver impairment.

Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study.

BACKGROUND: Ventriculitis is a complication of temporary intraventricular drains. The limited penetration of meropenem into the cerebrospinal fluid (CSF) is well known. However, ventricular CSF pharmacokinetic data in patients with ventriculitis are lacking. The aim of this study was to evaluate meropenem pharmacokinetics in the serum and CSF of neurocritical care patients with proven or suspected ventriculitis. METHODS: We conducted an observational pharmacokinetic study of neurocritical care patients with proven or suspected ventriculitis receiving meropenem. Multiple blood and CSF samples were taken and were described using nonparametric pharmacokinetic modelling with Pmetrics. RESULTS: In total, 21 patients (median age 52 years, median weight 76 kg) were included. The median (range) of peak and trough concentrations in serum were 20.16 (4.40-69.00) mg/L and 2.54 (0.00-31.40) mg/L, respectively. The corresponding peak and trough concentrations in CSF were 1.20 (0.00-6.20) mg/L and 1.28 (0.00-4.10) mg/L, respectively, with a median CSF/serum ratio (range) of 0.09 (0.03-0.16). Median creatinine clearance ranged from 60.7 to 217.6 ml/minute (median 122.5 ml/minute). A three-compartment linear population pharmacokinetic model was most appropriate. No covariate relationships could be supported for any of the model parameters. Meropenem demonstrated poor penetration into CSF, with a median CSF/serum ratio of 9 % and high interindividual pharmacokinetic variability. CONCLUSIONS: Administration of higher-than-standard doses of meropenem and therapeutic drug monitoring in both serum and CSF should be considered to individualise meropenem dosing in neurocritical care patients with ventriculitis.

Decreased Linezolid Serum Concentrations in Three Critically Ill Patients: Clinical Case Studies of a Potential Drug Interaction between Linezolid and Rifampicin.

Linezolid is a valuable treatment option for treating infections caused by multi-resistant gram-positive pathogens. Lack of effective linezolid levels due to the co-administration of rifampicin has been described in healthy subjects. However, the clinical significance of this potential drug interaction (DI) for critically ill patients is still unclear. This was a retrospective analysis of 3 critically ill patients with the combination therapy of linezolid and rifampicin or rifampicin pre-treatment. Despite increasing the dose of linezolid, the majority of observed linezolid trough concentrations in all 3 patients were below 2 mg/l. Furthermore, linezolid trough concentrations remained below 2 mg/l after discontinuation of rifampicin. This potential DI between linezolid and rifampicin could lead to treatment failure. Therefore, we strongly recommend that linezolid serum concentrations be monitored in patients with rifampicin co-administration or rifampicin pretreatment.

What is the effect of obesity on piperacillin and meropenem trough concentrations in critically ill patients?

OBJECTIVES: The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients. METHODS: This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa. RESULTS: In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L); P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05). CONCLUSIONS: This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.

Anti-infective drugs during continuous hemodialysis - using the bench to learn what to do at the bedside.

PURPOSE: The main objective of this study was to investigate the clearance of 11 selected anti-infectives in an in vitro model of continuous veno-venous hemodialysis (CVVHD), in order to suggest rational dosing strategies for clinical practice. METHODS: Ceftazidime, ciprofloxacin, flucloxacillin, gentamicin, linezolid, meropenem, metronidazole, piperacillin, rifampicin, vancomycin and voriconazole were studied in two different solvents (sodium chloride 0.9% and HSA 5%) using a multifiltrate dialysis device by Fresenius Medical Care (Bad Homburg, Germany). For each solution, prefilter, postfilter, and dialysate samples were drawn simultaneously during one hour of dialysis and were assayed. RESULTS: The clearance of all drugs except rifampicin in sodium chloride 0.9% was comparable (mean 1.76 ± 0.11 l/h). The clearance of these agents in human serum albumin solution 5% was reduced by between 5.3% and 72.2%. The unbound drug fraction correlated with a lower clearance in HSA 5% (Pearson correlation coefficient r = 0.933; p = 0.00008). No correlation between clearance in HSA 5% and the drugs' molecular weight was found (Pearson correlation coefficient r = 0.388; p = 0.268). Rifampicin was detected to bind to the surface of the polysulfone filter used. Dialysis clearance of ceftazidime, gentamicin, linezolid, meropenem, metronidazole, piperacillin and vancomycin during CVVHD accounted for over 25% of the total body clearance of population pharmacokinetic data for renally impaired patients. CONCLUSIONS: The results from this study highlight that dose adaptations are needed for most of the drugs under investigation for patients undergoing CVVHD. In combination with polysulfone filters, rifampicin should be used with care in this setting.